PROJECT SUMMARY Approximately 10-12% of all live births occur before completion of 37 weeks of gestation and because of the advances of neonatal medicine, fortunately, a significant proportion of these individuals survive to adulthood. Preterm birth results in underdeveloped lungs causing a number of cardiopulmonary limitations that persist into adulthood including low pulmonary function and aerobic exercise capacity. However, the medical management of these cardiopulmonary impairments are evidence-free because the underlying mechanisms/causes are unknown. This is problematic because the population of adult survivors of preterm birth (PRET) will continue to grow with advances in neonatal medicine, as will the associated health care costs. Likewise, cardiopulmonary function declines with age, which may result in PRET developing disabling cardiopulmonary function at an earlier age than their counterparts born at full term (CONT). The proposed work is important because it will identify potential targets for therapeutic interventions to improve and/or maintain cardiopulmonary function in PRET. Preliminary and published data from the PI?s lab, suggests that low resting cardiopulmonary function in PRET may not be due to abnormal respiratory muscle strength/function or pulmonary system compliance, but, rather, smaller airways than CONT. Additionally, previous work from the PI suggests that aerobic exercise capacity in PRET is limited by mechanical constraints to ventilation. Specifically, preliminary data suggests PRET have an excessive work of breathing. Based upon this previous and preliminary work our central hypotheses are that 1) low pulmonary function in PRET is not due to abnormal respiratory muscle strength/function and/or pulmonary system compliance, but rather 2) due to airways that are anatomically small and not constricted, and 3) low aerobic exercise capacity in PRET is due to an excessive work of breathing, caused by an excessive airway resistive work, that can be reduced with low-density gas. To test our central hypotheses the following Specific Aims are proposed: (1): Identify that respiratory pressure generation and pulmonary compliance are not major contributors to low resting pulmonary function in adult survivors of preterm birth. Based on previous work and our preliminary data, our working hypothesis is that mPRE, vPRE, and BPD have normal respiratory muscle strength and total pulmonary compliance; (2): Identify that airflow resistance is the major contributor to low resting pulmonary function in adult survivors of preterm birth. Based on previous work and our preliminary data, our working hypothesis is that mPRE, vPRE, and BPD have small airways and a normal incidence of airway hyperresponsiveness; and (3): Determine whether or not an excessive work of breathing limits aerobic exercise capacity in PRET individuals. Based on previous work and our preliminary data, our working hypothesis is that mPRE, vPRE, and BPD have an excessive Wb that is a primary cause of their lower-than-normal aerobic exercise capacity.